Submissions for variant NM_024675.4(PALB2):c.127A>G (p.Lys43Glu)

gnomAD frequency: 0.00001  dbSNP: rs765125459

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474623	SCV000550603	uncertain significance	Familial cancer of breast	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 43 of the PALB2 protein (p.Lys43Glu). This variant is present in population databases (rs765125459, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 410107). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000485071	SCV000572499	uncertain significance	not provided	2018-09-25	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.127A>G at the cDNA level, p.Lys43Glu (K43E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant has been observed in at least one individual with breast cancer (Tung 2015). PALB2 Lys43Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the region that interacts with BRCA1 and RAD51 (Sy 2009, Buisson 2010). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PALB2 Lys43Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000580520	SCV000685867	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 43 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 5/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV000485071	SCV000807072	uncertain significance	not provided	2016-12-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580520	SCV001170952	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	The p.K43E variant (also known as c.127A>G), located in coding exon 3 of the PALB2 gene, results from an A to G substitution at nucleotide position 127. The lysine at codon 43 is replaced by glutamic acid, an amino acid with similar properties. One study detected this alteration in 1/2158 women with breast cancer who underwent multigene panel testing (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002481445	SCV002793406	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-10-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000474623	SCV004189516	likely benign	Familial cancer of breast	2023-11-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000474623	SCV004202142	uncertain significance	Familial cancer of breast	2023-12-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485071	SCV004222259	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 25186627 (2015), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). The frequency of this variant in the general population, 0.00012 (4/34588 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Leiden Open Variation Database	RCV000474623	SCV001192933	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.